The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-xcex1 converting enzyme (TACE, tumor necrosis factor-xcex1 converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, J. F., Jr. FASEB J. 1991, 5, 2145; Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A. Crit. Rev. Oral Biol. Med. 1993, 4, 197; Cawston, T. E. Pharmacol. Ther. 1996, 70, 163; Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1]. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D. S.; Pelletier, J. -P. In Arthritis and Allied Conditions; McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D. Sem. Arthritis Rheum. 1991, 20, 2; Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323].
It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which may lead to tumor metastasis [Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Himeistein, B. P.; Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.; Muschel, R. J. Invasion Metast. 1994-95, 14, 246; Nuovo, G. J.; MacConnell, P. B.; Simsir, A.; Valea, F.; French, D. L. Cancer Res. 1995, 55, 267-275; Walther, M. M.; Levy, A.; Hurley, K.; Venzon, D.; Linehen, W. M.; Stetler-Stevenson, W. J. Urol. 1995, 153 (Suppl. 4), 403A; Tokuraku, M; Sato, H.; Murakami, S.; Okada, Y.; Watanabe, Y.; Seiki, M. Int. J. Cancer, 1995, 64, 355; Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R. J. Proc. Am. Assoc. Cancer Res. Ann. Meet. 1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y. Am. J. Pathol. 1996, 148, 611; Gress, T. M.; Mueller-Pillasch, F.; Lerch, M. M.; Friess, H.; Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407; Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.; Okada, Y. Virchows Arch., 1994, 424, 547-552.]. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis [Dollery, C. M.; McEwan, J. R.; Henney, A. M. Circ. Res. 1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H. J.; Clowes, A. W. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 28; Lee, R. T.; Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 1070.]. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren""s syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
The hypothesis that MMPs are important mediators of the tissue destruction that occurs in arthritis has long been considered, since it was first recognized that these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F., Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.; Woessner, J. F., Jr., Arthritis Rheum. 1983, 26, 63.], and continues to develop as new MMPs are identified. For example, collagenase-3 (MMP-13) was cloned from breast cancer cells in 1994, and the first report that it could be involved in arthritis appeared in 1995 [Freiji, J. M.; Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C. R.; Sandy, J. D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, Fla. Feb. 13-16, 1995.]. Evidence is accumulating that implicates MMP-13 in the pathogenesis of arthritis. A major structural component of articular cartilage, type II collagen, is the preferred substrate for MMP-13 and this enzyme is significantly more efficient at cleaving type II collagen than the other collagenases [Knauper, V.; Lopez-Otin, C.; Smith, B.; Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell, P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S. A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J.E . J. Clin. Invest. 1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B. V.; Mainardi, C. L.; Hasty, K. A. Arthritis Rheum. 1995, 38 (Suppl. 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. J. Clin. Invest. 1996, 97, 2011]. Potent inhibitors of MMPs were described over 10 years ago, but the poor bioavailability of these early peptidic, substrate mimetic MMP inhibitors precluded their evaluation in animal models of arthritis. More bioavailable, non-peptidic MMW inhibitors may be preferred for the treatment of diseases mediated by MMPs.
TNF-xcex1 converting enzyme catalyzes the formation of TNF-xcex1 from membrane bound TNF-xcex1 precursor protein. TNF-xcex1 is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti-TNF-xcex1antibodies and transgenic animals has demonstrated that blocking the formation of TNF-xcex1 inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (October), 197. This observation has recently been extended to humans as well. Other conditions mediated by TNF-xcex1 are congestive heart failure, cachexia, anorexia, inflammnation, fever, inflammatory disease of the central nervous system, and inflammatory bowel disease.
It is expected that small molecule inhibitors of gelatinase and TACE therefore have the potential for treating a variety of disease states. While a variety of M and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic or peptide-like compounds that may have bioavailability and pharmacokinetic problems that would limit their clinical effectiveness. Low molecular weight, potent, long-acting, orally bioavailable inhibitors of gelatinases, collagenases and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states. Several non-peptidc, sulfur-containing hydroxamic acids have recently been disclosed and are listed below.
U.S. Pat. No. 5,455,258, 5,506,242 and 5,552,4,19, as well as European patent application EP606,046A1 and WIPO international publications WO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997), 40, 2525. Additional publications disclosing sulfonamide based MMP inhibitors which are variants of the sulfonamide-hydroxamate shown below, or the analogous sulfonamide-carboxylates, are European patent application EP-757984-A1 and WIPO international publications WO95/35275, WO95/35276, WO96/27583, WO97/19068 and WO97/27174. 
Publications disclosing xcex2-sulfonamide-hydroxamate H inhibitor analogs of CGS 27023A in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen, as shown below, include WIPO international publications WO96/33172 and WO97/20824. 
The German patent application DE19,542,189-A1 discloses additional examples of cylic sulfonamides as MMP inhibitors. In this case the sulfonamide-containing ring is fused to a phenyl ring to form an isoquinoline. 
Analogs of the sulfonamide-hydroxamate MMP inhibitors in which the sulfonamide nitrogen has been replaced by a carbon atom, as shown in the general structure below, are European patent application EP-780386-A1 and WIPO international publication WO97/24117. 
This invention provides TACE and MMP inhibitors having the formula
B
wherein B is 
T, U, W, and X are each, independently, carbon or nitrogen, provided that when T or U is carbon, either may be optionally substituted with R1;
Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen; 
xe2x80x83is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms
which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri-substituted with R1;
Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri-substituted with R1;
R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, xe2x80x94(CH2)nZ, xe2x80x94OR2, xe2x80x94CN, xe2x80x94COR2, perfluoroalkyl of 1-4 carbon atoms, xe2x80x94CONR2R3, xe2x80x94S(O)xR2 xe2x80x94OPO(OR2)OR3, xe2x80x94PO(OR2)R3, xe2x80x94OC(O)NR2R3, xe2x80x94COOR2, xe2x80x94CONR2R3, xe2x80x94SO3H, xe2x80x94NR2R3, xe2x80x94NR2COR3, xe2x80x94NR2COOR3, xe2x80x94SO2NR2R3, xe2x80x94NO2, xe2x80x94N(R2)SO2R3, xe2x80x94NR2CONR2R3, xe2x80x94NR2C(xe2x95x90NR3)NR2R3, xe2x80x94SO2NHCOR4, xe2x80x94CONHSO2R4, -tetrazol-5-yl, xe2x80x94SO2NHCN, xe2x80x94SO2NHCONR2R3, or Z;
V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di- substituted with R2;
R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V;
n=1-6;
x=0-2
or a pharmaceutically acceptable salt thereof.
The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and TNF-xcex1 converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties. The definitions of alkyl, alkenyl, alkynyl, and cycloalkyl include alkyl, alkenyl, alkynyl, and cycloalkyl moieties which are unsubstituted (carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly- substituted with R1. Halogen means bromine, chlorine, fluorine, and iodine. Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole. Preferred xe2x80x9cheteroaryl fused to phenylxe2x80x9d rings indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzirmidazole, benzothiazole, benzisoxazole, and benzoxazole. The term xe2x80x9csaturated or partially unsaturated heterocycloalkyl ringxe2x80x9d means a saturated or partially unsaturated (but not aromatic, or fully saturated) heterocycle having 5-7 ring atoms, and containing 1-3 heteroatoms selected from N, O, or S. Preferred saturated or partially unsaturated heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or pyrrolidine. When a moiety contains more than substituent with the same designation (i.e., phenyl tri-substituted with R1) each of those substituents (R1 in this case) may be the same or different.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in B, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention are those in which:
B is 
xe2x80x83or a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those in which:
B is 
W and X are carbon; and
T is nitrogen;
U is carbon, optionally substituted with R1 
or a pharmaceutically acceptable salt thereof.
Still more preferred compounds of this invention are those in which:
B is 
W and X are carbon; and
T is nitrogen;
U is carbon, optionally substituted with R1 
xe2x80x83is phenyl or pyrazole, each optionally mono-, di-, or tri-substituted with R1;
or a pharmaceutically acceptable salt thereof.
When R5 is Z, it is preferred that Z is phenyl or pyridyl, each optionally mono-, di-, or tri-substituted with R1.
It is preferred that the Z moiety bonded to the sulfur of the sulfonamide of B, is phenyl optionally mono-substituted with R1 and R1 is OR2 or Z. When R1 is Z it is preferred that Z is phenyl, or pyridyl, each optionally mono-, di-, or tri-substituted with R1. When R1 is OR2, it is preferred that R2 is alkyl of 1-8 carbon atoms or Z, with Z being phenyl or pyridyl, each optionally mono-, di-, or tri-substituted with R1.
The compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. Typical known starting materials are shown below (I-XXI). These schemes, which follow thereafter, show the preparation of representative compounds of this invention. 
Compound I
a) Springer, R H; Scholten, M B; O""Brien, D E, Novinson, T; Miller, J P; Robins, R K J. Med. Chem. (1982), 25(3), 235-42.
b) Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687.
Compound II
Masui, T; TAkura, T; JP 46043792; JP 690307; CAN 76:59604
Compound III
Camparini, A; Ponticelli, F; Tedeschi, P J. Chem. Soc., Perkin Trans.1 (1982), 10, 2391-4.
Compound IV
Abdalla, G M; Sowell. J W J. Heterocycl. Chem. (1990), 27 (5), 1201-7.
Compound V
a) Denzel, T; Hoehn, H J. Heterocyclic Chem. (1977), 14, 813-817.
b) Al-Shaar, A H M; Chambers, R K; Gilmour, D W; Lythgoe, D J; McClenaghan, I; Ramsden, C A J. Chem. Soc.; Perkin Trans. I (1992) 21, 2789-2812.
c) Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687.
Compound VI
a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J. Med. Chem (1990) 2640-2645.
b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.
Compound VII
a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J. Med. Chem (1990) 2640-2645.
b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.
Compound VIII
Richardson, T O; Neale, N; Carwell, N J. Heterocyclic. Chem. (1995), 32, 359-361.
Baker, J M; Huddleston, P R; Keenan, G J J. Chem Research Miniprint, (1982) 6, 1726-1746.
Compound IX
a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J. Med. Chem (1990) 2640-2645.
b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.
Compounds X, XI and XII
Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687.
Compound XIII
Heterocycles, (1997), 45, 980.
Compound XIV
Yokoyama, Naokata. Eur. Pat. Appl., 61 pp. CODEN: EPXXDW. EP 115469 A1 840808.
Compound XV
Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 A1 891213.
Compound XVI
Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 A1 891213.
Compound XVII
Morita, Yoshiharu; Wagatsuma, Kazuo. Japan. Kokai, 4 pp. CODEN: JKXXAF. J P 50058094 750520 Showa.
Compounds XVIII and XIX
Armitage, Bernard John; Leslie, Bruce William; Miller, Thomas Kerr; Morley, Christopher. PCT Int. Appl., 110 pp. CODEN: PIXXD2. WO 9500511 A1 950105.
Compound XX
Minami, S.; Matsumoto, J.; Kawaguchi, K.; Mishio, S.; Shimizu, M.; Takase, Y.; Nakamura, S. (Dainippon Pharmaceutical Co., Ltd., Japan) Japan. Kokai, 3pp. CODEN: JKXXAF. JP 50014697 750215 Showa.
Compound XXI
Kihara, N.; Tan, H.; Takei, M.; Ishihara, T. (Mitsui Pechochemical Industries, Ltd., Japan; Suntory, Ltd.) Jpn. Kokai Tokyo Koho, 11 pp. CODEN: JKXXAF. J P 62221686 A2 870929 Showa.
The compounds of this invention can be prepared using conventional techniques known to those skilled in the art of organic synthesis. The following scheme (Scheme I) illustrates the reaction sequence employed. In the schemes which follow, the moiety A is defined as the bicyclic heteroaryl moiety of B, as shown immediately below:
A is 
For purposes of illustration only, wherein the bicyclic heteroaryl group A shown is a quinoline, 4-chloro-7-trifluoromethylquinoline-3-carboxylic acid ethyl ester, prepared from the corresponding aniline, is reacted with N-benzyl-p-methoxybenzenesulfonamide, wherein Z is p-methoxybenzene, to provide the requisite N,N-disubstituted sulfonamido-ester which is then converted into the corresponding hydroxamic acid in two steps.
Alternatively, the 4-chloroquinoline carboxylic acid ester could be first reacted with R7xe2x80x94NH2 and the resulting 4-(R7-amino)quinoline carboxylic acid ester then reacted with the appropriate Zxe2x80x94SO2xe2x80x94Cl. Hydrolysis of the ester and reaction with hydroxylamine hydro-chloride would then give the invention compound. 
Functionalization of the quinoline ring via a palladium catalyzed Heck coupling between the iodoquinoline and tributylvinyltin is shown in Scheme II. xcex1,xcex2-Unsaturated esters and amides can be coupled to the haloquinoline via Heck reactions. A variety of other trialkyltin reagents are readily available and may be similarly used. Boronic acids, commercially available or readily prepared, may also be coupled to the iodoquinoline using the Suzuki reaction. 
Functionalization of haloquinolines may also be accomplished via palladium catalyzed couplings of alkynes, as illustrated in Scheme III. Hydrogenation of the alkynes accesses the olefins and alkanes as well. 
Schemes IV and V illustrate two methods for incorporating amino groups into the substituent attached to the sulfonamide nitrogen of the compounds of the invention. Thus, in Scheme IV the NH-sulfonamide is alkylated with propargyl bromide to provide the propargyl sulfonamide. This alkyne is reacted with paraformaldehyde in the presence of a primary or secondary amine and cuprous chloride to give the propargyl amine which is converted, as before, to the desired hydroxamic acid. 
In Scheme V, selective hydrolysis of the ester of the p-carboethoxybenzyl sulfonamide group provides a mono-carboxylic acid. This acid may be converted into an amide (not shown), followed by conversion of the second ester, Axe2x80x94CO2R, into the corresponding hydroxamate, or reduced to the corresponding alcohol with diborane. The alcohol may be converted into the analogous amine via the benzylic bromide, followed by conversion of the the ester, Axe2x80x94CO2R, into the corresponding hydroxamate. 
Methods for synthesizing variations of substituents on the sulfonyl aryl group are shown in Schemes VI through VIII. As shown in Scheme VI, biaryl sulfonyl groups are synthesized by Suzuki couplings on a bromo-substituted benzene sulfonamide. The starting bromo-substituted benzene sulfonamide is synthesized from the commercially available bromobenzenesulfonyl chloride and the amino-acid or amino-ester, H2Nxe2x80x94Axe2x80x94CO2R, followed by alkylation of the resulting NH-sulfonamide. Alternatively, the bromo aryl sulfonamide is converted into the corresponding boronic acid by the method of Ishiyama, et.al. [J. Org. Chem. (1995), 60, 7508] followed by coupling with an appropriate aryl halide. 
Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VII through IX. In Scheme VII biaryl ethers, or aryl heteroaryl ethers, are synthesized starting from the known sulfonyl chlorides (see for example: Zook S E; Dagnino, R; Deason, M E, Bender, S L; Melnick, M J WO 97/20824). 
Alternatively, the biaryl ethers may be prepared from the corresponding boronic acids or via the sulfonyl phenols as shown in Scheme VIII. 
Aryl ethers may also be prepared via displacement of the fluorine from a para-fluorobenzene sulfonamide, as shown in Scheme IX. Aryl or alkyl ethers may be prepared in this manner. 
Scheme X illustrates the synthesis of pyrazolopyridines, isoxazolopyridines, and isothiazolopyridines of the invention. Thus, an aminopyrazole, arinoisoxazole or aminoisothiazole is condensed with ethoxymethylene malonate to provide the intermediate, B. This compound is converted into the pyrazolopyridine, isoxazolopyridine, or isothiazolopyridine, C, by heating at 240xc2x0 C. Compound C is then converted into the chloro-ester, D, via reaction with phosphorus oxychloride. Displacement of the chloro substituent with a sulfonamide then gives compound E. Hydrolysis of the ester and conversion of the carboxylate into the hydroxamate then gives compound G. Salts of the invention compounds can be prepared according to standard procedures. 
Pyrazolo[1,5-b]pyrimidines of the invention are prepared according to scheme XI using reactions as described for scheme X. 
The following specific examples illustrate the preparation of representative compounds of this invention. The starting materials, intermediates, and reagents are either commercially available or can be readily prepared following standard literature procedures by one skilled in the art of organic synthesis.